In the past few decades, there has been extensive research in the area of bioerodable matrices for the controlled release of bioactive compounds. These systems are of interest not only because they provide for the sustained release of therapeutic compounds, thereby increasing patient compliance, but also because they obviate the need to retrieve the carrier system after drug depletion.
The most common materials utilized for these matrices are biodegradable polymers, which are manufactured either as implantable devices or as suspensions of drug-containing polymeric microparticles. Synthetic polymers contemplated for use as matrices include those comprised of polylactic acid or copolymers of lactic and glycolic acids, polyanhydrides, polyamides, polyorthoesters, and polyphosphazenes (see e.g., U.S. Pat. Nos. 4,389,330, 4,093,709; 4,138,344; and Smith et al., Adv. Drug Del. Rev, 1990). Biodegradable polymers of biological origin are also well known, for example Yamahira in U.S. Pat. No. 4,855,134 discloses the sustained-release of α-interferon from matrices of gelatin, collagen and albumin. Woiszwillo in U.S. Pat. No. 5,578,709 teaches the use of matrices comprised of dehydrated, crosslinked proteins or polysaccharides for the release of many types of drugs, including macromolecules. Hyaluronic acid has also been crosslinked and used as a degradable swelling polymer for drug delivery applications (U.S. Pat. No. 4,957,744 to Della Valle et al).
Non-polymeric in-situ forming implant systems have also been disclosed (U.S. Pat. No. 5,736,152 to Dunn and U.S. Pat. No. 5,747,058 to Tipton and Holl). In these systems, a non-polymeric, biodegradable carrier material is dissolved in an organic solvent into which drug has been either dispersed or dissolved to form a liquid. Upon injection into the body the organic solvent dissipates, thereby producing a solid implant from which drug is released. Exemplary non-polymeric carriers disclosed are cholesterol and its derivatives, various fatty acids and fatty acid alcohols, phospholipids and derivatives thereof, sucrose acetate isobutyrate, and long-chain fatty acid amides. Other non-polymeric implants utilizing triglyceride-based matrices, oligoglycerol esters of fatty acids, and various vegetable (sesame, soy, peanut oils etc.) or synthetic (miglyol) oils gelled with aluminum mono-fatty acid esters (U.S. Pat. Nos. 5,411,951, 5,628,993 and 5,352,662) have also been described.
Proteins, peptides, polypeptides and other proteinaceous substances (e.g., viruses, antibodies), collectively referred to herein as proteins, have great utility as therapeutic agents in the prevention, treatment, and diagnosis of diseases. Unfortunately, these molecules possess limited stability, and are susceptible to both chemical degradation (e.g., via deamidation, oxidation, hydrolysis, disulfide exchange, and racemization of chiral amino acid residues) and physical degradation (e.g., via denaturation, aggregation, and precipitation), often resulting in a loss of biological activity. It is no surprise, therefore, that the delivery of these molecules from prior art systems has met with limited success. For example, the delivery of proteins from polyester-based implants and microspheres often leads to their chemical inactivation due to the acidic environment that develops during matrix erosion, and/or to their physical degradation due to adsorption to the polyester matrix surface. In other cases, either the presence of water or the partial hydrophilicity of the matrix makes it difficult to guarantee that water mediated degradation and/or denaturation processes would not occur either in-situ or in environments, such as the subcutaneous space, where contact with and imbibement of water is possible. And, although oleaginous delivery vehicles might theoretically protect protein drugs from aqueous degradation pathways (hydrolysis, deamidation, racemization etc.), many of the vehicles themselves are, to limited degrees, hydrophilic and unstable at body temperature. For example, the storage of liquid vegetable oils at physiological temperatures can result in the formation of amphiphilic and reactive species such as free fatty acids and peroxides (a process accelerated by the presence of traces of various metal ions such as copper or iron) which, in turn will catalyze the oxidative degradation or structural degradation of many proteins.
In addition, certain drugs, for example cytotoxic agents, cannot currently be developed as controlled release oral pharmaceutical products due to their high reactivity (low stability) in excipients typically employed for achieving sustained release from tablets or capsules. The alternative, parenteral delivery (often after reconstitution of lyophilized material), or an immediate-release oral formulation, may present efficacy or toxicity issues due to rapid fluctuations in plasma levels. Convenience and compliance issues can arise if multiple injections or tablets/capsules are required daily.
Consequently, there is a need to develop compositions, devices or systems that can overcome these limitations of the prior art. Such compositions should maintain the stability of the active compound at both room temperature and at body temperature (i.e., at 25 and 37° C.) for prolonged periods, and provide for the sustained release of active agents, such as reactive or unstable bioactive therapeutic agents.